Even with the currently most effective treatment regimens, about 10-20% of patients will fail to obtain eradication of Helicobacter pylori infection. Therefore, in designing a treatment strategy, we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of second-line treatment depends on which treatment was used initially, as re-treatment with the same regimen is not recommended. Therefore, it is not necessary to perform culture after the first eradication failure. Assessment of the sensitivity of H. pylori to antibiotics only after failure of the second treatment is suggested in clinical practice. Different possibilities of empirical treatment have been suggested. After failure of proton pump inhibitor-amoxicillin-clarithromycin, quadruple therapy has generally been used. More recently, replacement of the proton pump inhibitor and the bismuth compound by ranitidine bismuth citrate has also achieved good results. After proton pump inhibitor-amoxicillin-nitroimidazole failure, re-treatment with proton pump inhibitor-amoxicillin-clarithromycin has been proven to be effective. Finally, first-line treatment should not combine clarithromycin and metronidazole in the same regimen, because of the problem of resistance to both antibiotics. Recently, rifabutin-based rescue therapies have been shown to constitute an encouraging strategy for eradication failures, as they are effective against H. pylori strains resistant to antibiotics.